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Nat Commun. 2017 Sep 22;8(1):664. doi: 10.1038/s41467-017-00461-3.

Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth.

Author information

1
DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universität Dresden, Dresden, 01307, Germany.
2
Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of Technische Universität Dresden, Dresden, 01307, Germany.
3
Pain & Neuroscience Lab, Daiichi Sankyo Co., Ltd., Tokyo, 140-8710, Japan.
4
Weatherall Institute of Molecular Medicine, Oxford, OX3 9DS, UK.
5
DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universität Dresden, Dresden, 01307, Germany. nikolay.ninov@crt-dresden.de.
6
Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of Technische Universität Dresden, Dresden, 01307, Germany. nikolay.ninov@crt-dresden.de.
7
German Center for Diabetes Research (DZD e.V.), Neuherberg, Neuherberg, 85764, Germany. nikolay.ninov@crt-dresden.de.

Abstract

The proliferative and functional heterogeneity among seemingly uniform cells is a universal phenomenon. Identifying the underlying factors requires single-cell analysis of function and proliferation. Here we show that the pancreatic beta-cells in zebrafish exhibit different growth-promoting and functional properties, which in part reflect differences in the time elapsed since birth of the cells. Calcium imaging shows that the beta-cells in the embryonic islet become functional during early zebrafish development. At later stages, younger beta-cells join the islet following differentiation from post-embryonic progenitors. Notably, the older and younger beta-cells occupy different regions within the islet, which generates topological asymmetries in glucose responsiveness and proliferation. Specifically, the older beta-cells exhibit robust glucose responsiveness, whereas younger beta-cells are more proliferative but less functional. As the islet approaches its mature state, heterogeneity diminishes and beta-cells synchronize function and proliferation. Our work illustrates a dynamic model of heterogeneity based on evolving proliferative and functional beta-cell states.Βeta-cells have recently been shown to be heterogeneous with regard to morphology and function. Here, the authors show that β-cells in zebrafish switch from proliferative to functional states with increasing time since β-cell birth, leading to functional and proliferative heterogeneity.

PMID:
28939870
PMCID:
PMC5610262
DOI:
10.1038/s41467-017-00461-3
[Indexed for MEDLINE]
Free PMC Article

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